The mesolimbic pathway through the release of dopamine from neurons in the ventral tegmental area (VTA), which project to the nucleus accumbens (NAc), is thought to have a role in motivation and reward processes. Some addictive drugs produce their potent effects on behavior by enhancing mesolimbic dopamine activity. Release of dopamine from VTA neurons is controlled by various factors and neuronal structures. One pathway providing regulatory input to the VTA originates in the mesopontine nuclei of the brainstem. The candidate has shown that the mesopontine-VTA-NAc pathway is modulated by the novel neuropeptide urotensin II (UII). The candidate has also shown utility of a fusion of diphtheria toxin with Ull. This toxin is able to selectively ablate UII-R expressing neurons without damage to surrounding tissue. Through the combination of this toxin with microdialysis and behavioral paradigms, we will establish whether Ull can modulate reinforced behaviors. In other work Ull has been shown to produce cellular remolding, which may point to a role in neuroplasticity. Therefore, future studies will include the investigation of the role of UII-R in molecular neurobiological changes and the development of addiction. The University of California, Irvine is home to a unique concentration of established scientists in the field of novel neuropeptide function. This collaborative environment will expose the candidate to many different aspects of the characterization of novel neuropeptide systems. Throughout his graduate career, and subsequent post-doctoral research, the candidate has been responsible for the primary research, initiating and fostering of collaborations, and the writing of manuscripts. Therefore, the transition to establishing independent research in to the molecular neuropharmacology of the Ull system should be smooth. The mentors'roles will be to provide space and resources for the completion of research of sufficient quality to allow the candidate to successfully compete for a faculty position at an outstanding research university. PUBLIC HEALTH RELEVANCE: The current proposal is relevant in that the novel neuropeptide urotensin II may be a previously unrecognized player in the regulation of motivational processes. The investigation of which may add another layer of understanding the complex action of psychoactive drugs.